The novel positron emission tomography (PET) ligand [11C] Arachidonic Acid (AA) has been partially characterized in healthy volunteers16-18 and in Alzheimer's disease19, in which upregulated AA signaling has been observed, associated with neuroinflammation. Another promising application for this ligand is the study of Bipolar Disorder (BD); the hypothesis that regulation of the AA cascade is abnormal in BD has accumulated considerable supporting evidence. In animal studies, mood stabilizers lithium, valproate, carbamazepine, and lamotrigine downregulate the brain AA cascade5. AA is not simply a ubiquitous responder to drugs, as negative results were obtained with topiramate20, later shown to be clinically ineffective for BD. In BD patients, manic symptom severity correlates positively with levels of plasma unesterified AA11; markers of AA metabolism8 and neuroinflammation12 are increased postmortem; and clinical deterioration is retarded by aspirin, an anti- inflammatory inhibitor of AA metabolism14. Goal. The project goal is to acquire pilot data concerning use of [11C]AA to study neuropathophysiology of BD. Specific aims propose to do the following: 1) characterize [11C]AA incorporation in patients with BD and compare with healthy volunteers; 2) extend the characterization of the [11C]AA radiotracer; and 3) explore baseline [11C]AA brain incorporation as a predictor of clinical response to lithium. Methods. PET scans will take place at Weill Cornell Medical College, where the ligand is currently in use for the study of Alzheimer's. Healthy volunteers (n=10) and depressed, medication-free outpatients with BD (n=10) will each have a [11C]AA scan, a [18F]fluoro- deoxyglucose scan to measure regional brain activity, and an MRI scan. Six healthy volunteers will have repeat scans six weeks later, for test-retest data. BD patients will be treated with lithium for 6 weeks at NYS Psychiatric Institute after scanning. Scans will be analyzed using established methods16. Plasma AA levels will be analyzed at NIH for use as a covariate in analyses. Significance. The pathophysiology of BD is poorly understood, and current treatments are inadequate. These pilot data are expected to clarify the feasibility of using [11C]AA to study BD pathophysiology. Positive associations between baseline AA incorporation and lithium response would have important implications for BD treatment: 1) molecular components of the AA cascade may be novel targets for rational design of drugs to treat BD; 2) AA cascade responses in rats could be useful as a bioassay for testing potential mood stabilizers and perhaps also antidepressants; and 3) AA cascade abnormalities might serve as a biomarker for clinical response that would facilitate individualized treatment. PUBLIC HEALTH RELEVANCE: This project collects preliminary information, using a novel PET scanning agent ([11C]AA), to improve understanding of whether the Arachidonic Acid biochemical pathway contributes to the development of Bipolar Disorder. Bipolar Disorder is a disabling, lifelong illness that carries a high suicide mortality rate and is often difficult or evn impossible to control with present treatments. [11C]AA is a potential biomarker that could assist in discovery of new drugs to treat Bipolar Disorder.